1. Field of the Invention
The present invention relates generally to medical procedures and more specifically to methods of using a context-dependent functional entity to enhance the efficacy of one or more agents in a subject.
2. Background Information
Although cancer remains a leading cause of morbidity and mortality in the world, it appears that more efficacious drugs and treatment protocols are providing increased hope that many, if not all, cancers eventually will be treatable. In some cases, the advances in treatment are due to improved surgical techniques or improved methods of radiation therapy. Advances also have been due to the identification of one or more drugs that are particularly effective for treating cancer. Taxol(copyright), for example, which is a natural product prepared from the Pacific yew tree, can prolong survival of patients with ovarian cancer, which has a very low survival rate. Platinol(copyright), which is a cis-platinum product, is effective in treating metastatic testicular cancer, and also is indicated in bladder cancer that has progressed to a stage that no longer can be treated by surgery.
Further advances in cancer therapy have been made by combining therapies, including surgery and radiation therapy, surgery and drug therapy, radiation therapy and drug therapy, and combined drug therapies. Where feasible, surgery often is used initially to remove the bulk of a tumor, then radiation therapy or chemotherapy is used to kill cells that may be outside of the region of surgery, including metastatic lesions. Treatment of a cancer patient with a drug such as hydroxyurea, which appears to inhibit DNA synthesis in cells, sensitizes the inhibited cells, including cancer cells, to the effects of radiation and, therefore, often is combined with radiation therapy.
Where surgery or radiation therapy cannot provide a significant treatment modality due, for example, to the location or extent of a cancer, combined drug modalities often are the treatment of choice. Generally, drugs are combined based on their having different mechanisms of action. Thus, an antimetabolite, which kills cancer cells by inhibiting DNA synthesis, can be combined with an agent that kills cells by inhibiting cell division. Such combined modalities generally have an additive effect due to each of the agents killing a population of cells sensitive to the drug.
Occasionally, combined modalities can result in a greater than additive effect. For example, treatment with Herceptin(copyright), which is a monoclonal antibody that recognizes a particular cell surface receptor expressed on breast cancer cells, in combination with two chemotherapeutic agents, kills a greater number of cells than would be expected due to simple additive effects. Where combined modality treatment results in a greater than additive effect of cancer cell killing, the dose of each drug often can be reduced. The ability to reduce the doses of chemotherapeutic agents, while still maintaining a therapeutic effect against a cancer, provides a significant therapeutic benefit, since it is the toxic side effects of cancer chemotherapeutic agents to normal cells that often limits the dose of drug that can be administered to a patient and, therefore, limits the treatment. By decreasing the amounts of drugs that need to be administered to a patient to effectively treat a cancer, side effects such as bone marrow depletion, loss of appetite, and hair loss are less severe, thereby improving the patient""s quality of life.
Agents such as Herceptin(copyright), which, when combined with other agents, enhance the efficacy of a second drug by producing a greater effect than otherwise would be expected, would be particularly useful for treating diseases such as cancer. Unfortunately, few agents that generally produce such an effect have been identified. Thus, a need exists to identify agents that can be administered, for example, in combination with one or more therapeutic drugs and increase the effectiveness of the drugs. The present invention satisfies this need and provides additional advantages.
The present invention relates to a method of enhancing the efficacy of one or more agents in a subject by administering to the subject the agent or agents and a context-dependent functional entity (xe2x80x9cCDFExe2x80x9d). A CDFE is a chimeric molecule that is composed of modular components and that acts as an integrated unit, which exhibits a functional activity in a position and orientation dependent manner. A CDFE can interact with a function-forming context expressed on a cell or in a tissue in the subject and, as disclosed herein, enhance the efficacy of an agent administered with the CDFE in a subject.
The modular components of a CDFE include a substructure with thrombogenic potential operably linked to a selective recognition domain. The substructure with thrombogenic potential can be a coagulation factor, for example, a vertebrate tissue factor (TF) or a modified form of TF such as a peptide portion of TF having thrombogenic potential. The selective recognition domain can be a kringle domain, for example, a plasminogen kringle 5 domain, or a peptide portion thereof such as the amino acid sequence Pro-Arg-Lys-Leu-Tyr-Asp (SEQ ID NO: 1); or can have, for example, the amino acid sequence as set forth in SEQ ID NO: 2. The substructure with thrombogenic potential is operably linked to the selective recognition domain, or other modular component, either directly or through a spacer element.
A CDFE can interact with a function-forming context expressed on the surface of a cell or in a tissue in the subject, for example, in vascular tissue such as tumor associated vascular tissue, thereby enhancing the efficacy of one or more agents at the site of the cell or tissue. The agent can be, for example, a diagnostic agent, a nutritional molecule, a toxin, a radiation sensitizer, or a therapeutic agent such as a cancer chemotherapeutic agent or other agent or combination of agents, and can be in an encapsulating matrix such as a liposome, which can be a modified liposome. For example, a method of the invention can include administering a cancer chemotherapeutic agent such as doxorubicin, which may or may not be encapsulated in a modified liposome, and a CDFE, either in combination or sequentially in any order; by any of various routes, including, for example, parenterally, intravenously or orally; systemically or at the site of a tissue in which it is desired to enhance the efficacy of the agent; and the timing of administration of the CDFE and the agent can be varied.
The invention also relates to methods of treating a pathologic condition in a subject by administering to the subject a therapeutic agent and a CDFE, which contains a substructure with thrombogenic potential operably linked to a selective recognition domain, whereby interaction of the CDFE with a function-forming context expressed on a cell or in a tissue in the subject enhances the efficacy of the therapeutic agent in the subject, thereby treating the pathologic condition. The pathologic condition can be a cell proliferative disorder, for example, a neoplasm, which can be benign or malignant. The substructure with thrombogenic potential can be a coagulation factor or a portion thereof, for example, a vertebrate TF or a modified form thereof, and the selective recognition domain can be a kringle domain or a portion thereof. Where the pathologic condition to be treated is a malignant neoplastic disease, the therapeutic agent is a cancer chemotherapeutic agent or a combination of chemotherapeutic agents, for example, an antimetabolite, an alkylating agent, an antitumor antibiotic, a cytokine, a hormone, a hormone antagonist, a nitroso compound, a plant alkaloid, a platinum compound, or the like, and can be encapsulated in a liposome, which can be a modified liposome. Where a subject is to be treated by radiation therapy, a therapeutic agent can be a radiation sensitizing agent.
The invention further relates to pharmaceutical compositions, which contain a CDFE and one or more agents in a pharmaceutically acceptable form, wherein the CDFE comprises a substructure with thrombogenic potential and a selective recognition domain. For example, the CDFE can include a modified form of tissue factor and kringle domain, which can be operably linked through a peptide spacer element. The agent can be a diagnostic agent, a nutritional molecule, a toxin, a radiation sensitizer, a therapeutic agent, or the like, or combinations thereof
The invention also provides a peptide having the amino acid sequence Pro-Arg-Lys-Leu-Tyr-Asp (SEQ ID NO: 1). Such a peptide is useful, for example, as a selective recognition domain, which can facilitate an interaction of a CDFE with a function-forming context. Polypeptide sequences containing SEQ ID NO: 1 are encompassed within the claimed invention, provided the polypeptide sequence is not plasminogen or a peptide portion of plasminogen containing SEQ ID NO: 1. In particular, chimeric molecules, including, for example, fusion polypeptides, comprising SEQ ID NO: 1 are encompassed within the invention.